Exome sequencing and copy number alterations demonstrate branched evolution with early divergence between spatially separated regions of individual foci. The mutational patterns are consistent with subclonal mixing, with broad spatial occupancy by subclonal populations. Subclonal events are biologically and clinically relevant, involving conserved positions, cancer-associated genes, and convergent evolution. In addition, the same pathways that are altered in advanced disease are affected by subclonal alterations in localized disease. More aggressive localized disease harbors more of these clinically relevant subclonal alterations than lower stage, less aggressive disease. These data are consistent with a model in which subclonal populations from the primary tumor are enriched by therapeutic pressure, giving rise to advanced, therapy-resistant disease.